Supportive health care measures instituted during childhood successfully prevent serious infections and many other life-threatening complications of sickle cell disease (SCD), resulting in improved survival to adulthood. This has, in part, shifted the demographics of SCD to include a growing proportion of young adults with chronic health impairments. While hematopoietic cell transplantation (HCT) has curative potential, very few individuals with SCD are treated by HCT, due in part to the toxicity of this treatment. Recently, advances in Human Leukocyte Antigen (HLA) typing techniques and supportive care have improved outcomes of HCT, particularly after unrelated donor HCT. We have organized an interdisciplinary group of transplant investigators and adult sickle cell providers as well as a daa coordinating center very experienced in the conduct of clinical trials for the BMT clinical trials network to test the hypothesis that HCT from an HLA-identical sibling or unrelated marrow donor with a conditioning regimen of Busulfan, Fludarabine and anti-thymocyte is safe and effective in young adults with severe SCD with a two year event free survival of at least 80%. We have tested the feasibility of recruitment and safety of the conditioning regimen in a pilot study of BMT in adults with SCD. We propose to test this hypothesis in a clinical trial that it wil compare outcomes after HCT to outcomes observed in those who receive standard supportive care, the first comparison of this kind in hemoglobin disorders. We will assign 60 patients age 15-40 years who have an available suitably matched donor to the BMT arm and will contemporaneously enroll 120-140 SCD who do not an available suitable donor to a parallel comparison cohort. We propose to investigate HCT in adults with severe sickle cell disease by the following specific aims: 1. Determine the safety and efficacy of HCT in young adults with severe sickle cell disease. 2. Measure the impact of donor hematopoiesis on functional outcomes and end-organ function. We will establish a long term follow up cohort of all eligible patients for the purpose of future studies of long term impact of HCT on outcome sin SCD. If successful, the proposed comparative clinical trial would be the first to compare HCT and supportive care for SCD, and could broaden the therapeutic opportunities for adults with severe SCD.